The goal of this ongoing project is to identify and characterize the genes that contribute to cancer risk in[unreadable] familial childhood cancer syndromes of sarcoma (Li Fraumeni Syndrome, LFS) and (new addition to this[unreadable] project) Wilms' tumor (WT). For each syndrome we have demonstrated known genes that contribute (p53[unreadable] and WT1), evidence for additional genetic contribution, and evidence for genetic heterogeneity. In families[unreadable] with germline p53 mutations we find evidence for significant heterogeneity in risk by gender and generation,[unreadable] with a younger age of onset in successive generations. We have examples of both syndromes in which we[unreadable] have ruled out p53 or WT1 as the susceptibility locus, and have identified new regions of the genome that[unreadable] may contribute. To identify other cancer susceptibility genes and risk modifiers, we propose to use data[unreadable] generated by continued longitudinal study and from the other projects and cores to perform combined[unreadable] genetic linkage and segregation analysis in the familial childhood cancer syndromes. The proposal includes[unreadable] using regressive logistic models, Monte Carlo Markov Chain methods, Kaplan Meier and proportional[unreadable] hazards survival analyses. We will incorporate measures of telomere function as they relate to cancer risk or[unreadable] to a given genotype. The specific aims are (1) to use linkage and segregation analysis to identify additional[unreadable] risk modifiers in the p53 mutation LFS kindreds, including mechanisms to account for the observed[unreadable] generation effect and factors associated with multiple primary tumors, and to characterize the phenotype and[unreadable] genotype of the non-p53 cancer prone (LFS) kindreds, (2) to identify the role of genetic and treatment related[unreadable] risk factors in the outcome of multiple additional neoplasms in the sarcoma cohorts, and (3) to identify the[unreadable] genetic model(s) that best characterize familial Wilms' tumor and provide a guide for identification of the[unreadable] relevant genetic pathways in Wilms tumor. These analyses provide feedback to the projects regarding the[unreadable] contribution of newly identified genomic regions or genes.[unreadable] The importance of cancer genetic susceptibility and second primary cancers, using rare syndromes as[unreadable] models, was recognized by an NCI survivorship conference on that topic in 2004. This P01 has the unique[unreadable] combination of human and mouse genetics to identify new genes and genetic mechanisms of cancer[unreadable] susceptibility that will be significant for populations as well as the rare genetic syndromes.